A decrease in muscle mass, or atrophy, is associated with various physiological and pathological states. For example, muscle atrophy can result from denervation due to nerve trauma; degenerative, metabolic or inflammatory neuropathy, e.g. Guillian-Barré syndrome; peripheral neuropathy; or nerve damage caused by environmental toxins or drugs; from denervation due to a motor neuropathy including, for example, adult motor neuron disease, such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease); infantile and juvenile spinal muscular atrophies; autoimmune motor neuropathy with multifocal conductor block. Muscle atrophy may also result from chronic disease resulting from, for example, paralysis due to stroke or spinal cord injury; skeletal immobilization due to trauma, such as, for example, fracture, sprain or dislocation; or prolonged bed rest. Metabolic stress or nutritional insufficiency, which may also result in muscle atrophy, include inter alia the cachexia of cancer, AIDS, and other chronic illnesses, fasting or rhabdomyolysis, and endocrine disorders such as disorders of the thyroid gland and diabetes. Muscle atrophy may also be due to a muscular dystrophy syndrome such as Duchenne, Becker, myotonic, fascioscapulohumeral, Emery-Dreifuss, oculopharyngeal, scapulohumeral, limb girdle, and congenital types, as well as the dystrophy known as Hereditary Distal Myopathy. Muscle atrophy may also be due to a congenital myopathy, such as benign congenital hypotonia, central core disease, nemalene myopathy, and myotubular (centronuclear) myopathy.
Insulin-like growth factor 1 (IGF-1), is a small protein growth factor that has been shown to cause hypertrophy when expressed in skeletal muscle (Coleman et al. (1995) J. Biol. Chem. 270:12109-16). A signaling pathway activated in response to IGF-1 is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (PI3K/Akt). (Vanhaesebroeck et al. (1997) TIBS 22:267). PI3K causes phosphorylation of the cell membrane-bound molecule phosphatidylinositol 4,5-bisphosphate at the 3 position, resulting in phosphatidylinositol 3,4,5-trisphosphate. Akt then translocates to the cell membrane and binds to phosphatidylinositol 3,4,5-trisphosphate, where the Akt is activated.